The ultimate goal of this proposal is to evaluate the changes induced in the tumor microenvironment upon treatment with oncolytic viruses (OV) and assess how these changes impact OV therapy. These results will lead to a better understanding of OV therapy induced changes in tumor biology and will lead to the development of a dually armed cancer killing OV. OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Results from six clinical trials using replication competent OVs to treat patients with malignant gliomas have shown the new modality to be relatively safe, but high expectations of efficacy remain unmet (1, 2). The tumor's microenvironment is increasingly recognized as an important determinant for its progression and its response to therapeutics. We are investigating changes in the tumor microenvironment following oncolytic viral (OV) therapy, with the ultimate goal to devise better treatment strategies to combat brain tumors. My laboratory has been investigating changes in the tumor secreted angiotome (secreted angiogenic proteins) after OV therapy. In our preliminary studies, we have uncovered a significant increase in a secreted protein implicated in increased tumor proliferation, angiogenesis and resistance to chemotherapy. Its expression is correlated as a negative prognostic marker for gliomas, prostate, and breast cancer. Apart from its effect on tumor progression, our preliminary results indicate that it may also contribute to the development of resistance of glioma cells to OV infection in subsequent rounds of replication. In this grant proposal we will validate our findings of its induction in glioma with multiple different oncolytic viruses. We will further evaluate the effect of this protein on OV infection, and will finally construct and test an OV that can overcome the induction of this protein. PROJECT NARRATIVE: The American Cancer Society predicts that there will be 12, 740 deaths due to cancers of the brain/nervous system. Despite decades of research prognosis for patients suffering from malignant gliomas remains poor. Oncolytic viral therapy is an experimental treatment which is currently being evaluated in clinical trials for efficacy against brain tumors. The proposed research outlined in this grant is highly significant because it will elucidate the changes in tumor biology upon oncolytic viral therapy. The results will advance our understanding of changes in tumor biology upon treatment with oncolytic viruses. This will help translate oncolytic viral therapy into an efficacious treatment for tumors.